亚硝基化合物是引起肝癌的关键膳食因素。肿瘤干细胞对肿瘤的发生、发展起决定性作用。目前从肝癌干细胞角度探讨亚硝基化合物诱发肝癌的分子机制及其干预研究未见报道。我们前期研究发现慢性N-二甲基亚硝胺暴露能诱导人正常肝细胞恶性转化且具有肝癌干细胞特性，此表型与上调TAp63α、下调ΔNp63α及激活Sonic Hedgehog通路有关；大蒜主要活性成分二烯丙基三硫化物（DATS）可抑制恶转的肝癌干细胞活性。然TP63α/Sonic Hedgehog是否真正调控慢性N-二甲基亚硝胺诱导肝癌干细胞的活性及DATS的干预效应尚属未知。本课题采用体外细胞模型和动物模型相结合，创新性地探讨TP63α/Sonic Hedgehog通路调控N-二甲基亚硝胺诱导肝癌干细胞的作用机制，并在此基础上研究DATS的干预作用。旨在从肝癌干细胞视角探索亚硝基化合物诱发肝癌的分子机制并为其靶向干预提供新的重要科学依据。

Nitrosocompounds are critical dietary risk factor of liver cancer. Cancer stem cells (CSCs) play crucial role in the formation and development of cancer. To date, the action of nitrosocompounds on the induction of liver CSCs, the underlying mechanisms as well as diallyltrisulfede (DATS) intervention has not been defined. In our preliminary studies we found that chronic N-nitrosodimethylamine (NDMA) exposure induced malignant transformation of human normal liver cells (LO2), among which liver CSCs activity existed, along with upregulation of TAp63α, downregulation of ΔNp63α, and activation of Sonic Hedgehog signaling pathway. We also showed that DATS inhibited sphere formation capacity of malignant transformated LO2 cells cultured in serum-free-medium, reduced liver CSCs markers’ expression, suppressed TAp63α expression, upregulated ΔNp63α level, and prevented the activation of Sonic Hedgehog pathway. However, the role and regulation of TP63α/Sonic Hedgehog axis in chronic NDMA-induced liver CSCs and DATS intervention is unknown. Using both in vitro and nude mouse models, the present research will for the first time investigate the role of TP63α/Sonic Hedgehog in NDMA -induced liver CSCs and its regulatory mechanism. Furthermore, this research will illustrate the function of TP63α/Sonic Hedgehog in the interventional effects of DATS on NDMA-induced liver CSCs. Finding from this research will provide new insights into the molecular mechanisms of TP63α/Sonic Hedgehog in regulating NDMA-induced liver CSCs and search for new approach for its target intervention